Virus-induced delayed-type hypersensitivity reaction is sequentially mediated by CD8⁺ and CD4⁺ T lymphocytes

After subcutaneous inoculation into the hind foot of a mouse, the lymphocytic choriomeningitis (LCM) virus multiplies locally, attaining 10⁷-10⁸ mouse infectious units per g of tissue; elimination commences around day 7. About 1 day earlier, the foot begins to swell, which is regarded as a delayed-type hypersensitivity (DTH) reaction. To answer the question of whether the local inflammatory response is involved in virus clearance, we needed to known what cells mediate both these phenomena. With three different procedures - namely, depletion in vivo of defined cells by treatment of mice with monoclonal antibodies ('serologic surgery'), adoptive immunization with negatively selected cells, and adoptive immunization with cells from mice differing at the major histocompatibility gene complex - it is shown that the LCM virus-induced local DTH reaction consists of two phases that are sequentially mediated by (first) class I-restricted cytotoxic/suppressive CD8⁺ and (second) class II-restricted helper/inducer CD4⁺ T lymphocytes. In contrast, for virus elimination only the former subset of T lymphocytes was found to be needed. Thus, an association may exist between the CD8⁺ cell-mediated component of the local DTH response and control of the infection, but the CD4⁺ cell-mediated part appears to be of doubtful antiviral relevance.